5-amino-1,2,3-triazole-4-carboxamide derivatives were originally discovered as antiparasitic agents and then subsequently demonstrated to be antiproliferative agents and potential cancer therapeutics. The specific compound, 5-amino-[4-(4-chlorobenzoyl)-3,5-dichlorobenzyl]-1,2,3-triazole-4-carboxamide (Formula I illustrated below, shown as the free base form), has been demonstrated to have antiproliferative and antimetastatic activity that was linked to decrease of intracellular calcium by inhibition of non-voltage-gated calcium channels. It is an inhibitor of transmembrane calcium influx and intracellular calcium requiring signalling pathways. Tyrosine kinase and metalloproteinase pharmacological mechanistic activities and anti-angiogenesis activity relevant to antitumor efficacy have also been described for this compound. The compound of Formula I will be referred to in the following discussion using the acronym CAI (carboxy-amido-triazole) which is generally used to describe the compound.

Clinical investigations have been conducted with CAI in the treatment of life-threatening diseases. For example, CAI has been used in the treatment of a variety of refractory tumors, including prostate cancer, lymphomas, glioblastoma, peritoneal cancer, fallopian tube cancer, epithelial ovarian cancer, advanced renal cell carcinoma, metastatic renal carcinoma, and non-small cell lung cancer (Bauer, K. S. et al. Clin Cancer Res. 5:2324-2329, 1999; Kohn, E. C. et al. Cancer Res. 52:3208-3212, 1992; Kohn, E. C. et al. J Biol Chem. 269:21505-21511, 1994; Kohn, E. C. et al. Proc Natl Acad Sci USA. 92:1307-1311, 1995; Kohn, E. C. et al. Cancer Res. 56:569-573, 1996; Kohn, E. C. et al. J Clin Oncol. 15:1985-1993, 1997; Kohn, E. C. et al. Clin Cancer Res. 7:1600-1609, 2001.
While these studies using CAI indicate that CAI has intrinsic clinical efficacy for many cancer types, the systemic oral dosage regimens and formulations used in a clinical setting to date have been associated with dose limiting side effects. Moreover, toxic effects (cerebellar ataxia, peripheral neuropathy and exacerbation of depression) have been observed in clinical studies at doses of CAI required to achieve circulating levels that are within a narrow range or those projected from pharmacological studies to be required for effective inhibition of pathological neovascularization. Furthermore, a serious side effect associated with clinical use of CAI by systemic administration has been the loss of vision for which two cases have been described (Berlin, J. et al. Clin Cancer Res. 8:86-94, 2002). Therefore, use of CAI as currently applied in clinical investigations for cancer is effectively precluded for acute or chronic treatment of non-life threatening conditions, in particular for the treatment of ocular diseases described herein.
To treat certain ocular diseases, such as age-related macular degeneration (or ARMD), and diabetic retinopathy, or diseases with specific ocular manifestations, such as von Hippel landau syndrome, therapeutic treatments rely on occlusion of the blood vessels using either threshold laser photocoagulation, or subthreshold laser combined with a photoactivated dye. However, such treatment requires either full-thickness retinal damage by thermal destruction, or damage to medium and large choroidal vessels thereby precluding any potential visual recovery. Further, the subject is left with a scar and visual scotoma. Moreover, recurrences are common, and visual prognosis is poor.
Recent research in the treatment of neovascularization has had the aim of causing a more selective closure of the blood vessels, in order to preserve the overlying neurosensory retina. Such strategies have been used for the treatment of diabetic retinopathy, the leading cause of blindness among working age adults in Europe and the United States. However, extensive ocular tissue damage can occur after panretinal photocoagulation, with the visual handicap of more limited peripheral vision and poor night vision. With focal laser treatment, photocoagulation often can further compromise macular blood flow. Alternatively, a variety of molecules are in development or have been approved that target angiogenic pathways (e.g. the VEGF pathway). Thus, using antiangiogenic compounds is an alternative to lasering of patients.
CAI is an anti-angiogenic and anti-parasitic compound; however, the poor aqueous solubilities of CAI compounds, as well as reported neurotoxicity for CAI, means that novel methods of administration and targeted administration of CAI compounds are required for providing safe and effective doses to treat disease and non-life threatening diseases in particular.
High local concentrations of CAI may be required to treat acute disease symptoms while lower concentrations can be effective as continuation therapy or prophylactic therapy. Additionally the frequency of administration of a formulation of a CAI compound can also be used to ensure safe and effective local concentrations to slow vascular outgrowth. Treatment may be necessary from every week, to every month to few months, to yearly dosing with appropriate molecules in sustained delivery systems.
Posterior segment neovascularization (NV) is the vision-threatening pathology responsible for the two most common causes of acquired blindness in developed countries: exudative ARMD and proliferative diabetic retinopathy (PDR). Currently the only approved treatments for posterior segment NV that occurs during exudative ARMD are laser photocoagulation, photodynamic therapy with VISUDYNE®, and the VEGF binding oligonucleotide aptamer Macugen®. Laser and photodynamic therapies involve occlusion of affected vasculature, which results in localized laser-induced damage to the macula. For patients with PDR, surgical interventions with panretinal laser, or vitrectomy and removal of preretinal membranes, or treatment with Macugen® are the only treatment options currently available. However, in addition to the recently approved anti-VEGF aptamer oligonucleotide Macugen®; several different compounds are being evaluated clinically, including, for example, anecortave acetate (Alcon Research, Ltd.), and Lucentis® (ranibizumab, Genentech), Squalamine lactate (Genaera Corporation), LY333531 (Lilly), Cand5 (Acuity Pharmaceuticals), Talaporfin sodium (Light Sciences Corp.), and Fluocinolone (Bausch & Lomb).
Treatments using dosage regimens, routes of administration and formulations of CAI described to date do not have adequate safety for treating severe proliferative diseases that are non-life threatening. There exists an unfulfilled need for new dosage regimens, routes of administration and formulations of CAI that can provide therapeutic effects on non-life threatening proliferative diseases, as exemplified by ocular diseases that are characterized by neovascularization and pathological cellular proliferation and invasion. There also exits an unfilled need for administering CAI formulations that can provide therapeutic effects on uveitis, which is characterized by the swelling of the middle layer of the eye and which according to Barisani-Asenbauer et al. “is the fourth most common cause of blindness among the working-age population in the developed world.” Orphanet Journal of Rare Diseases 2012, 7:57.